1. Field of the Invention
This invention is directed to substituted 4-amino-1-benzylpiperidine and related compounds which are useful as muscarinic receptor antagonists. This invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds for treating medical conditions mediated by muscarinic receptors; and processes and intermediates for preparing such compounds.
2. State of the Art
The muscarinic receptor family comprises five known receptor subtypes, i.e., M1, M2, M3, M4 and M5 receptors, with each receptor subtype having a distinct distribution and function. For example, smooth muscle tissues typically express both M2 and M3 receptor subtypes and these receptors serve to mediate the contraction of these tissues.
As a result, compounds that act as muscarinic receptor antagonists are known to be useful for treating various medical conditions associated with improper smooth muscle function, such as overactive bladder (OAB), irritable bowel syndrome (IBS) and chronic obstructive pulmonary disease (COPD). These smooth muscle function disorders are highly prevalent in society resulting in enormous economic costs. For example, in the United States alone, an estimated 30 million people, primarily women and the elderly, suffer from overactive bladder and approximately $10 billion are spent annually treating this condition. More importantly, the quality of life and self-esteem of patients afflicted with these disorders is often significantly impaired
Until recently, most compounds that act as muscarinic receptor antagonists were relatively non-selective for the various muscarinic receptor subtypes. As a result, such compounds often produced unpleasant side-effects, such as dry-mouth, constipation, blurred vision, or cognitive side effects. The most common of these side-effects is dry-mouth which results from inhibition of M3 receptors in the salivary gland. This dry-mouth side effect is often so severe that an estimated 80 to 85 percent of patients being treated for overactive bladder discontinue their medication within six months and, as a result, their condition goes untreated.
Accordingly, a need exists for new muscarinic receptor antagonists. In particular, a need exists for new muscarinic receptor antagonists which selectively inhibit M2 receptors relative to M3 receptors. Such compounds are expected to be particularly effective for treating smooth muscle disorders mediated by M2 and M3 receptor subtypes, such as overactive bladder, while reducing or eliminating the dry-mouth, constipation and blurred vision side-effects mediated predominately by the M3 receptor subtype.